The SNP rs6508974 in AXL is a functional polymorphism and a promising biomarker for gefitinib treatment

Abstract

Somatic mutations in epidermal growth factor receptor (EGFR) found in lung adenocarcinomas are used as biomarkers for the treatment with EGFR-tyrosine kinase inhibitors, including gefitinib. The bypass tracks with amplification of AXL is one of the mechanisms underlying the resistance to gefitinib. We, therefore, carried out a candidate gene approach method to identify AXL polymorphisms associated with the effectiveness of gefitinib. EGFR mutations were first identified by mutant-enriched PCR-restriction fragment length polymorphism (RFLP), and then 2 tag single nucleotide polymorphisms (SNPs) of AXL were examined by PCR-RFLP in 62 Japanese patients with advanced lung adenocarcinoma and treated with gefitinib in two general hospitals in Nagasaki. Subsequently, the association of EFGR mutations and the AXL polymorphism with the effectiveness of gefitinib was examined in these patients. We next examined the effect of the AXL polymorphism on the expression and function of this gene. It is worthy of note that EGFR mutations and the AXL polymorphism rs6508974 independently contributed to the effectiveness of gefitinib, and the polymorphism was proved to be a possible biomarker for selecting non-responders and responders to gefitinib treatment even in the absence of EGFR mutations. Furthermore, this SNP increased the transcriptional activity of the AXL transcript variant 3, one of the three AXL transcript variants, which to some extent increased the epithelial-mesenchymal transition in cancer cells. Taken together, AXL is one of the genes that determine the effectiveness of gefitinib and a biomarker for selecting non-responders and responders among lung adenocarcinoma patients with no EGFR mutations, suggesting that rs6508974 in AXL might be a functional SNP in lung adenocarcinoma.